Respiratory Syncytial Virus (RSV) is a human pathogen that is the predominant cause of acute lower respiratory tract infection in children [reviewed by (27)]. In the United States, nearly all children are infected with RSV by the age of three. Symptoms range from severe pneumonia and bronchiolitis to milder infections. Because of its prevalence, RSV is a major cause of serious respiratory illness requiring hospitalization in children. Significant morbidity and mortality are also associated with RSV infection of the elderly.
The viral genome encodes two major structural glycoproteins that are exposed on the surface of RSV virions, G and F. G is believed to play a role in viral attachment to a cellular receptor. F promotes fusion of the viral and cell membranes, allowing entry of the viral genome into the target cell. Antibodies against either G or F can neutralize RSV infectivity (18). The G protein is highly genetically diverse amongst RSV strains, thus anti-G neutralizing antibodies are only neutralizing against viruses of one of the two antigenic groups of RSV (either A or B). In contrast, F is highly conserved and anti-F neutralizing antibodies can protect animal models from infection by both group-A and group-B viruses (26, 31).
There is no current vaccine for RSV infection. (In the 1960s a formalin-inactivated RSV vaccine candidate actually increased disease severity in vaccinated children.) Moreover, there are no useful therapeutics for treating RSV infection. However, Palivizumab, also known by its trade name Synagis, a monoclonal antibody that targets a neutralizing epitope in the F glycoprotein, has been used prophylactically to prevent RSV infection. Although Synagis is effective, it is very expensive and only is cost-effective for use in infants that are at extremely high risk for developing severe RSV infection. Because of its expense, it is only used in developed countries.
Virus-like Particle (VLP) Based Vaccines.
Virus-like particles (VLPs) make excellent vaccines. They are non-infectious, often easier to produce than actual viruses, and, because the regularity of their capsid structure presents viral epitopes as dense, highly repetitive arrays that strongly stimulate B cells, they are highly immunogenic. VLPs are comprised of one or more proteins arranged geometrically into dense, repetitive arrays. These structures are largely unique to microbial antigens, and the mammalian immune system has apparently evolved to respond vigorously to this arrangement of antigens. B cells specifically recognize and respond strongly to the ordered array of densely spaced repetitive elements characteristic of virus surfaces (1, 16). Highly repetitive antigens provoke oligomerization of the membrane-associated immunoglobulin (Ig) molecules that constitute the B cell receptor (BCR) (2). There is evidence that the Ig crosslinking mediated by multivalent antigens leads to the formation of highly stable BCR-signaling microdomains that are associated with increased signaling to the B cell (34). This signaling stimulates B cell proliferation, migration, and upregulation of both major histocompatibility complex (MHC) class II and the co-stimulatory molecules that permit subsequent interactions with T helper cells that are required to trigger IgG secretion, affinity maturation, and the generation of long-lived memory B cells (8). Consequently, multivalent antigens such as VLPs can activate B cells at much lower concentrations than monomeric antigens (3, 13, 14, 25). Hence, VLPs are innately immunogenic: they induce high titer and long lasting antibody responses at low doses, often without requiring adjuvants (19, 36).
VLPs as Flexible Platforms for Vaccine Development.
VLPs can be used as the basis for vaccines targeting the virus from which they were derived (the Hepatitis B virus vaccine and HPV vaccine are two clinically approved VLP vaccines, other VLP vaccines are in clinical trials). However, they also can be used as platforms to display practically any epitope in a highly immunogenic, multivalent format. Heterologous antigens displayed at high density on the surface of VLPs exhibit the same high immunogenicity as unmodified VLPs. VLPs derived from a variety of different viruses have been exploited in this manner to induce antibody responses against heterologous targets that are poorly immunogenic in their native contexts. Although the VLP platform strategy has typically been applied to target antigens derived from pathogens, VLP-display can effectively induce antibody responses against practically any antigen. One example is the vaccine for nicotine addiction (designed to assist smokers who are trying to quit) developed by a biotechnology company, Cytos Biotechnology. This vaccine consists of nicotine, conjugated at high copy number to the surface of VLPs derived from a bacteriophage. In phase II clinical trials, VLPs displaying nicotine were well-tolerated and induced strong nicotine-specific IgG responses in 100% of immunized subjects (12). Even self-antigens, which are normally subject to the mechanisms of B cell tolerance, are immunogenic when displayed at high density on the surface of VLPs. Vaccines have been developed against self-molecules involved in several different diseases, including amyloid-beta (Alzheimers (11, 21)), TNF-α (arthritis (9)), CCR5 (HIV infection (7, 10)), gastrin (cancer, unpublished data), IgE (allergy, unpublished data), and others. VLP-based vaccines developed by pharmaceutical companies targeting amyloid-beta and angiotensin II (hypertension) are currently being evaluated in clinical trials; positive results from the trial of vaccine targeting angiotensin II (as a vaccine for hypertension) were reported in the spring of 2008 (35).